Short-term treatment outcomes of the ranibizumab biosimilar CKD-701 for vitreous hemorrhage secondary to proliferative diabetic retinopathy

Abstract

Purpose

To evaluate the short-term clinical outcomes of CKD-701, a ranibizumab biosimilar, in treating vitreous hemorrhage (VH) secondary to proliferative diabetic retinopathy (PDR).

Methods

This retrospective study included 64 eyes of 64 patients with VH secondary to PDR who received intravitreal CKD-701 injections and were followed for at least four months. Visual acuity (VA) was assessed at baseline, at the first follow-up (mean 3.8 weeks), and at 2- and 4-months post-treatment. The incidences of recurrent VH and vitrectomy were recorded. The factors associated with the degree of visual improvement were analyzed.

Results

The patients received a mean of 1.8 ± 0.9 injections. VA significantly improved over time (mean logMAR VA: 1.29 ± 0.82 at baseline, 1.11 ± 0.84 at first follow-up, 0.94 ± 0.81 at 2 months, and 0.73 ± 0.68 at 4 months; P < 0.001). The proportions of patients achieving 20/40 or better VA at each time point were 18.8%, 25.0%, 29.7%, and 40.6%, respectively. Recurrent VH occurred in 17.2% of patients, and vitrectomy was performed in 12.5%. There was no significant difference in 4-month VA between patients who did and did not undergo vitrectomy (P > 0.999). Baseline VA was significantly associated with the degree of visual improvement (P = 0.010). No severe ocular complications were observed.

Conclusions

In this short-term study, VH secondary to PDR decreased following CKD-701 treatment and was accompanied by visual improvement. Further well-controlled long-term studies are needed to definitively assess the efficacy of CKD-701.

Introduction

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is effective for a range of retinal diseases that are entirely or partially driven by VEGF-mediated pathological mechanisms. One therapeutic indication for anti-VEGF agents is vitreous hemorrhage (VH) secondary to proliferative diabetic retinopathy (PDR).

In a clinical trial involving patients with PDR conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net), the group receiving continuous intravitreal injections of ranibizumab demonstrated long-term visual outcomes comparable to those achieved with panretinal photocoagulation (PRP), the conventional gold-standard treatment [1]. Based on this finding, a consensus has emerged that anti-VEGF therapy is a viable treatment option for VH secondary to PDR [2].

Despite their proven efficacy, the high cost of anti-VEGF agents remains a major limitation [3]. As a result, bevacizumab—although not officially approved by the Food and Drug Administration for ocular indications—has been widely used due to its significantly lower cost compared to originator drugs [3, 4]. This trend underscores the need for more affordable, effective, and officially approved anti-VEGF agents.

Biosimilars are biologic drugs with molecular structures highly similar to those of the originator products. An approved biosimilar must demonstrate equivalent efficacy and safety compared to its originator [5]. Although negative perceptions—such as the nocebo effect—may exist regarding biosimilars [6], they are typically offered at a lower cost than originator products, reducing both individual and societal financial burdens and contributing to more cost-effective treatment [5, 7–9].

CKD-701 (Chong Kun Dang Pharm. Co., Ltd., South Korea) is a ranibizumab biosimilar approved by the South Korean Ministry of Food and Drug Safety (MFDS) in October 2022 [10]. In a clinical trial, the improvement in visual acuity (VA) at 3 months was + 7.0 ETDRS (Early Treatment Diabetic Retinopathy Study) letters in the CKD-701 group, comparable to the + 6.2 letters observed in the ranibizumab originator group [10]. Through indication extrapolation, CKD-701 has been approved by the MFDS for nearly all indications previously held by ranibizumab, including treatment of PDR.

To date, only a few cases using anti-VEGF biosimilars to treat VH secondary to PDR have been reported [11], and detailed treatment outcomes remain to be elucidated. This study aimed to address this gap by evaluating the treatment outcomes of CKD-701 for VH secondary to PDR.

Methods

This retrospective observational study was conducted at a single center, Kim’s Eye Hospital in Seoul, South Korea. This study was approved by the Institutional Review Board of Kim’s Eye Hospital and conducted in accordance with the principles of the Declaration of Helsinki.

Patients and treatments

This study included patients diagnosed with VH secondary to PDR who received intravitreal CKD-701 injections between November 2023 and December 2024. Exclusion criteria were as follows: (1) patients who received CKD-701 injections as pre-treatment for scheduled vitrectomy, and (2) a follow-up period of less than 4 months. If both eyes met the eligibility criteria, only the eye that received the treatment first was included in the study.

Following the first injection, patients underwent follow-up examinations 2–5 weeks later, with subsequent follow-up intervals determined at the discretion of the physician. At each visit, uncorrected VA was measured, and fundus examinations along with fundus photography using an ultra-widefield imaging device (Optos^®; Optos plc, Dunfermline, UK) were performed. Optical coherence tomography examinations were performed at the discretion of the physicians. In cases of severe vitreous hemorrhage, in which the retina could not be clearly visualized, OCT examinations were not ordered because it was often difficult to obtain clear OCT images.

If the treating physician determined that further treatment was required to reduce VH, additional CKD-701 injections were administered. New or additional panretinal photocoagulation (PRP) was performed when the physician considered it necessary or when the vitreous hemorrhage had cleared sufficiently to allow PRP to be performed. Vitrectomy was performed in cases in which the hemorrhage was deemed unlikely to resolve with injections alone.

In eyes with VH, measuring manifest refraction is often difficult because of media opacity, making it challenging to consistently and accurately measure the best-corrected VA. Therefore, uncorrected VA was used for analysis in this study.

Outcome measures

VA before the first CKD-701 injection was compared with VA measured at the first follow-up and at 2 and 4 months after the initial injection. The degree of vitreous hemorrhage (VH) was assessed at the aforementioned time points using fundus photographs. If a patient was unable to visit the clinic precisely at the 2- or 4-month time points, examination findings from the nearest available visit were used for analysis.

The VA at baseline was compared with that measured at the first follow-up, 2 months, and 4 months after the initial injection. The severity of VH was classified into five categories (Fig. 1) [12]: 0 = the nerve fiber layer is clear; 1 + = the nerve fiber layer is blurry, optic nerve and retinal vessels are clear; 2 + = optic nerve and retinal vessels are blurry; 3 + = only the optic nerve is seen; 4 + = the fundus is not accessible, and the optic nerve cannot be seen. Two independent examiners (J.H.K. and S.M.P.) performed the VH assessments. In cases of discrepancy, disagreements were resolved through discussions between the two examiners. The examiners performed grading while being blinded to the time point at which the fundus photographs were obtained.

Fig. 1.

Representative fundus photographs and optical coherence tomography (OCT) images illustrating the classification of VH severity. (A) 0 = The nerve fiber layer is clear. (B) 1 + = The nerve fiber layer is blurry; the optic nerve and retinal vessels are clear. (C) 2 + = The optic nerve and retinal vessels are blurry. (D) 3 + = Only the optic nerve is visible. (E) 4 + = Fundus is not accessible; even the optic nerve cannot be seen

The following data were collected: age, sex, presence of hypertension, lens status (phakia vs. pseudophakia), use of antiplatelet agents at the time of the first CKD-701 injection, history of prior panretinal photocoagulation (PRP), anti-VEGF therapy, or vitrectomy before the first CKD-701 injection, interval between the first injection and follow-up, number of CKD-701 injections during the 4-month follow-up period, incidence and timing of recurrent VH, and whether and when patients ultimately underwent vitrectomy to clear media opacity. Incidences of ocular complications such as endophthalmitis, intraocular inflammation, and retinal detachment were also recorded.

Factors associated with visual improvement from baseline to the first follow-up after CKD-701 injection were evaluated using the following variables: age, sex, presence of hypertension, lens status, use of antiplatelet agents, history of prior PRP, anti-VEGF therapy, or vitrectomy, baseline VA, and the interval between the injection and the first follow-up. Factors associated with the need for vitrectomy were assessed using the same variables, excluding the interval between the injection and the first follow-up.

The patients were divided into two groups according to their history of vitrectomy. Changes in VA between baseline and the first follow-up visit as well as the proportion of eyes exhibiting a decrease in the VH grade until the first follow-up were compared between the two groups. Patients were divided into two groups based on whether PRP was performed during the follow-up period. The number of CKD-701 injections, the incidence of recurrent VH, and changes in VA over the 4-month follow-up period were compared between the two groups.

Statistical analysis

Data are presented as the mean ± standard deviation or as the number (%), as appropriate. The counting fingers (CF) and hand motion (HM) VAs were converted to decimal values of 0.014 and 0.005, respectively [13]. Normality was assessed using the Shapiro–Wilk test. Comparisons among the four time points were performed using the Friedman test, while comparisons between two time points were conducted using the Wilcoxon signed-rank test with Bonferroni correction. Comparisons between the two groups were performed using the Mann-Whitney U test with or without Bonferroni correction or Fisher’s exact test. Multivariable analysis was performed using linear or binary logistic regression. Cohen’s kappa coefficient was calculated to assess agreement between the two examiners. Statistical analyses were performed using SPSS for Windows (version 21.0; IBM Corp., Armonk, NY, USA). Statistical significance was set at P < 0.05.

Results

A total of 64 eyes from 64 patients were included in this study (Table 1). The mean age was 58.1 ± 11.4 years, and 45 patients (70.3%) were male. Hypertension was present in 35 patients (54.7%) and antiplatelet agents were used in 21 patients (32.8%). The first follow-up visit occurred an average of 3.8 ± 1.5 weeks after the initial CKD-701 injection. The mean timing was 61.3 ± 6.3 days for the 2-month visit and 122.5 ± 10.9 days for the 4-month visit.

Table 1.

Baseline characteristics of included patients (64 eyes from 64 patients)

Characteristics	Values
Age at the time of CKD-701 injection	58.1 ± 11.4
Sex, men: women	45 (70.3%): 19 (29.7%)
Hypertension	35 (54.7%)
Lens status
Phakic	42 (65.6%)
Pseudophakic	22 (34.4%)
Use of anti-platelet agent	21 (32.8%)
History of ocular treatment
PRP	36 (56.3%)
Anti-VEGF therapy	34 (53.1%)
Vitrectomy	9 (14.1%)
Visual acuity, logMAR	1.29 ± 0.82
Degree of visual acuity
≥20/40	12 (18.8%)
≥20/100, < 20/40	12 (18.8%)
≥20/1000, < 20/100	14 (21.9%)
CF or HM	26 (40.6%)

Data are presented as the mean ± standard deviation or No. (%) where applicable

Abbreviations: PRP, panretinal photocoagulation; VEGF, vascular endothelial growth factor; CF, counting fingers; HM, hand motion

During the 4-month follow-up period, patients received an average of 1.8 ± 0.9 CKD-701 injections, and PRP was performed in 17 eyes (26.6%). Vitrectomy was performed in eight patients (12.5%) at a mean of 8.6 ± 2.4 weeks after the first CKD-701 injection. In 22 eyes (34.4%), only a single CKD-701 injection was administered during the 4-month follow-up period; however, in the remaining 42 eyes (65.6%), one or more additional injections or other treatments were required. The mean number of follow-up visits was 4.9 ± 2.2, which corresponds to approximately one visit every 3.3 weeks.

Mean logMAR VA was 1.29 ± 0.82 at baseline, 1.11 ± 0.84 at the first follow-up, 0.94 ± 0.81 at 2 months, and 0.73 ± 0.68 at 4 months (Fig. 2). There was a significant improvement in VA across the four time points (P < 0.001). Specifically, VA significantly improved at the first follow-up (P = 0.030), 2 months (P < 0.001), and 4 months (P < 0.001) compared to baseline. A total of 22 eyes had best-corrected visual acuity (BCVA) measured at baseline and the 4-month follow-up. In these eyes, the mean BCVA improved from 1.51 ± 0.69 at baseline to 0.71 ± 0.66 at 4 months.

Fig. 2.

Changes in visual acuity after the first CKD-701 injection. Visual acuity significantly improved following treatment. Statistical analysis was performed using paired t-tests with Bonferroni correction. Each follow-up time point represents the mean uncorrected visual acuity, with error bars indicating standard deviation. logMAR = logarithm of the minimal angle of resolution. The first visit indicates a mean of 3.8 weeks after the CKD-701 injection

At baseline, 18.8% of patients (12 eyes) had VA of ≥ 20/40; 18.8% (12 eyes) had VA between ≥ 20/100 and < 20/40; 21.9% (14 eyes) had VA between ≥ 20/1000 and < 20/100; and 40.6% (26 eyes) had CF or HM vision (Fig. 3A). At the first follow-up, these proportions changed to 25.0% (16 eyes), 23.4% (15 eyes), 17.2% (11 eyes), and 34.4% (22 eyes), respectively; at 2 months, to 29.7% (19 eyes), 31.3% (20 eyes), 15.6% (10 eyes), and 23.4% (15 eyes); and at 4 months, to 40.6% (26 eyes), 32.8% (21 eyes), 10.9% (7 eyes), and 15.6% (10 eyes), respectively.

Fig. 3.

Changes in the distribution of visual acuity (A) and vitreous hemorrhage grade (B) during the 4-month CKD-701 treatment period (N = 64). Note that over time, the proportion of patients with poor visual acuity decreases, as does the proportion with higher grades of vitreous hemorrhage. CF = counting fingers; HM = hand motion

Among the eight patients who underwent vitrectomy, mean logMAR VA was 1.79 ± 0.59 at baseline and 0.67 ± 0.68 at four months. In contrast, among the 56 patients who did not undergo vitrectomy, the corresponding values were 1.22 ± 0.83 at baseline and 0.74 ± 0.69 at four months. Baseline VA was significantly worse in the vitrectomy group (P = 0.044); however, no significant difference was observed at four months (P > 0.999).

At baseline, grades of patients were as follows: 7.8% of the patients (5 eyes) had grade 0 VH, 14.1% (9 eyes) had grade 1, 34.4% (22 eyes) had grade 2, 31.3% (20 eyes) had grade 3, and 12.5% (8 eyes) had grade 4 VH (Fig. 3B). At the first follow-up, these proportions changed to 17.2% (11 eyes), 29.7% (19 eyes), 17.2% (11 eyes), 18.8% (12 eyes), and 17.2% (11 eyes); at 2 months, to 40.6% (26 eyes), 23.4% (15 eyes), 7.8% (5 eyes), 18.8% (12 eyes), and 9.4% (6 eyes); and at 4 months, to 51.6% (33 eyes), 17.2% (11 eyes), 14.1% (9 eyes), 15.6% (10 eyes), and 1.6% (1 eye), respectively. Figure 4 shows a representative case of VH resolution following CKD-701 treatment. The Cohen’s kappa value for agreement between the two examiners was 0.875.

Fig. 4.

A representative case demonstrating the clinical outcomes following CKD-701 injection. A 68-year-old patient presented with vitreous hemorrhage (VH) secondary to proliferative diabetic retinopathy. At baseline (A), VH obscured clear visualization of the retina, and visual acuity (VA) was counting fingers. Four weeks after the first CKD-701 injection (B), VH had decreased, and VA improved to 20/400. During follow-up, the patient received three CKD-701 injections and underwent panretinal photocoagulation. At four months (C), VH further decreased, accompanied by VA improvement to 20/100. Optical coherence tomography (OCT) images are included in panels A and C. For panel B, OCT examination was not performed; therefore, no OCT images were available

Recurrent VH occurred in 11 patients (17.2%) at an average of 7.9 ± 4.1 weeks after the initial CKD-701 injection (Fig. 5). No cases of endophthalmitis, intraocular inflammation, or retinal detachment were observed after the CKD-701 injection.

Fig. 5.

A Kaplan–Meier graph showing the cumulative incidence of recurrent vitreous hemorrhage after the first CKD-701 injection

In multivariable analysis of VA improvement, baseline VA was significantly associated with the degree of improvement following CKD-701 treatment (P = 0.010, odds ratio 0.373, 95% confidence interval 0.061–0.422) (Table 2). Other variables—including age (P = 0.261), sex (P = 0.299), presence of hypertension (P = 0.278), lens status (P = 0.321), use of antiplatelet agents (P = 0.373), history of PRP (P = 0.126), history of anti-VEGF therapy (P = 0.144), history of vitrectomy (P = 0.294), and the interval between CKD-701 injection and the first follow-up (P = 0.976)—were not significantly associated with visual improvement.

Table 2.

Associations of variables with visual improvement after CKD-701 injection

Variables	P-value	OR	95% CI
Age	0.261
Sex, men: women	0.299
Hypertension	0.278
Lens status	0.321
Use of anti-platelet agent	0.373
History of PRP	0.126
History of anti-VEGF therapy	0.144
History of Vitrectomy	0.294
Baseline visual acuity	0.010	0.373	0.061–0.422
Interval between CKD-701 injection and the first follow-up	0.976

* Statistical analyses were performed using linear regression

Abbreviations: OR, odds ratio; CI, confidence interval; PRP, panretinal photocoagulation; VEGF, vascular endothelial growth factor

In multivariable analysis of the need for vitrectomy, a history of PRP was significantly associated with a reduced risk of requiring vitrectomy (P = 0.027, odds ratio 0.042, 95% confidence interval 0.003–0.697) (Table 3). Other variables—including age (P = 0.306), sex (P = 0.880), presence of hypertension (P = 0.653), lens status (P = 0.472), use of antiplatelet agents (P = 0.814), history of anti-VEGF therapy (P = 0.309), prior vitrectomy (P = 0.265), and baseline VA (P = 0.164)—were not significantly associated with the need for vitrectomy.

Table 3.

Associations of variables with need for vitrectomy after CKD-701 treatment

Variables	P-value	OR	95% CI
Age	0.306
Sex, men: women	0.880
Hypertension	0.653
Lens status	0.472
Use of anti-platelet agent	0.814
History of PRP	0.027	0.042	0.003–0.697
History of anti-VEGF therapy	0.309
History of Vitrectomy	0.265
Baseline visual acuity	0.164

* Statistical analyses were performed using binary logistic regression

Abbreviations: OR, odds ratio; CI, confidence interval; PRP, panretinal photocoagulation; VEGF, vascular endothelial growth factor

The mean change in VA between the baseline and the first follow-up was + 0.36 ± 0.71 in eyes with a history of vitrectomy and + 0.16 ± 0.50 in eyes without such history (P = 0.570). In eyes with a history of vitrectomy, 44.4% (4 eyes) showed a decrease in the VH grade, whereas the proportion was 34.5% (19 eyes) in eyes without a history of vitrectomy (P = 0.711). In eyes that underwent PRP during the follow-up period, the mean number of CKD-701 injections was 2.1 ± 0.9, the change in VA during the follow-up period was + 0.16 ± 0.50, and the incidence of recurrent VH was 23.5% (4 of 17 eyes). In eyes that did not undergo PRP, the corresponding values were 1.7 ± 0.9, + 0.19 ± 0.55, and 14.9% (7 of 47 eyes), respectively. No significant differences were found in the number of CKD-701 injections (P = 0.085), change in BCVA (P = 0.839), or incidence of recurrent VH (P = 0.463) between the two groups.

Among the total cohort, 50 patients (78.1%) were followed up for at least 12 months. Of these, 7 underwent vitrectomy within 4 months. Among the remaining 42 patients, 4 underwent vitrectomy between 4 and 12 months.

Discussion

Biosimilars have been introduced and are increasingly utilized across various medical fields [14]. In anti-VEGF therapy, their adoption is relatively recently, and their usage volume and market share are still being established. However, their use is anticipated to increase significantly over time. In India, where ranibizumab biosimilars were first introduced, surveys have reported high levels of satisfaction among retinal specialists [15].

Physicians’ preferences for biosimilars remain a topic of debate. A recent survey of oncologists found that 48.3% preferred originator drugs over biosimilars, citing greater trust in the efficacy and safety of the originators [16]. Additionally, 56.8% of specialists expressed negative views about switching from originator drugs to biosimilars [16]. Some physicians remain cautious about biosimilars due to concerns like the nocebo effect,⁶ and some patients are hesitant to switch for fear of experiencing new or unknown side effects. Addressing these challenges requires more real-world data on the efficacy and safety of biosimilars in clinical practice.

This study examined the treatment outcomes of ranibizumab biosimilars for VH secondary to PDR. A significant reduction in VH was observed following CKD-701 treatment. At baseline, the retinal nerve fiber layer was clearly identifiable in only 7.5% of eyes; this increased to 17.2% after the first injection and to 51.6% at the final visit. Following the initial injection, a significant improvement of approximately two lines in VA was observed within an average of 3.8 weeks of follow-up. Despite the relatively low number of injections (mean 1.8), VA continued to improve over time, with a marked gain of more than five lines observed at the four-month follow-up. Although vitrectomy was performed in 12.5% of cases, there was no significant difference in four-month VA between patients who underwent vitrectomy and those who did not. These findings suggest that treatment with a ranibizumab biosimilar alone can lead to a substantial reduction in VH and significant visual improvement in most patients.

Greater visual improvement after the injection was observed in eyes with poor baseline VA. More importantly, eyes that had previously underwent PRP had a significantly lower likelihood of requiring vitrectomy. This finding underscores the importance of PRP in managing patients with PDR.

The results of the DRCR.net’s Protocol S clinical trial,¹ which treated PDR using ranibizumab, provided strong evidence for establishing guidelines for the use of anti-VEGF therapy in PDR. Based on the findings from the Protocol S study, Sun et al. suggested that anti-VEGF therapy can be a useful first-line treatment even for PDR without accompanying diabetic macular edema [2]. They also recommended continuing anti-VEGF therapy in cases where vitreous hemorrhage occurs during treatment until the hemorrhage clears enough to adequately assess the retinal neovascular status. However, Protocol S was not specifically designed to evaluate anti-VEGF therapy for treating VH.

Previous studies focusing on VH secondary to PDR have demonstrated that anti-VEGF therapy is effective as a first-line treatment. An early clinical trial comparing ranibizumab and saline for treating VH secondary to proliferative diabetic retinopathy (PDR) showed that ranibizumab reduced the risk of vitrectomy within 16 weeks by approximately 5% (12% vs. 17%) [17]. Recurrent VH within 16 weeks occurred in 6% of patients in the ranibizumab group, compared to 17% in the saline group.

A more recent study by Chelala et al., reported vitrectomy rates of 23.94% in the ranibizumab-treated group versus 35.48% in the control group over four months [12]. For mild-to-moderate VH, vitrectomy was significantly less common in the ranibizumab-treated group (7.04%) than in the control group (19.35%).

In the study by Antoszyk et al., 100 patients received aflibercept injections as the primary treatment, with an average of 4.6 injections administered over 24 weeks [18]. During this period, only 14% of patients required vitrectomy. At 24 weeks, mean VA was 59.3 letters in the aflibercept group and 63.0 letters in the vitrectomy with PRP group. Although the vitrectomy group experienced faster visual improvement, no significant difference in VA was found between the groups at 24 weeks [18]. While anti-VEGF monotherapy requires ongoing injections to maintain retinal stability [19], its minimally invasive nature helps improve vision and reduce media opacity, often enabling PRP—supporting its role as a useful first-line treatment for VH secondary to PDR.

A systematic review by Quiroz-Reyes et al. comparing vitrectomy and aflibercept for dense VH found that at one month, VA was better in the vitrectomy group [20]. However, by six months, no significant difference in VA was observed between the groups. The aflibercept group had a higher risk of VH recurrence compared to the vitrectomy group. The authors concluded that aflibercept is a viable treatment option for diabetic VH in patients with reliable follow-up [20].

In the present study, the vitrectomy rate (12.8%) was consistent with previous reports [17, 18]. The incidence of recurrent VH (17.2%) in our study was higher than the 6% reported in a prior ranibizumab study [17]. However, the earlier study administered three consecutive ranibizumab injections at 4-week intervals [17], which may have contributed to a lower recurrence rate.

Patients with diabetes frequently face high healthcare costs for managing systemic comorbidities [21], which may limit their ability to afford additional ophthalmic treatments. Moreover, recent research has shown that patients with lower incomes are more likely to present with advanced diabetic retinopathy compared to higher-income patients [22]. These findings highlight the need to reduce treatment-related costs for patients with PDR and VH, supporting the use of biosimilars as a cost-effective alternative.

In this study, patients were treated with one or more of the following modalities: CKD-701 injection, PRP, and vitrectomy. Even after the initial CKD-701 injection, a considerable proportion of patients required additional treatments, including further injections and the aforementioned procedures. Anti-VEGF injections, PRP, and vitrectomy are widely used treatment options for the management of high-risk PDR [23]. The results of this study suggest that the effect of a single CKD-701 injection in the treatment of vitreous hemorrhage associated with PDR is limited in many patients and that continuous follow-up and additional treatments are required when necessary.

A key strength of this study is that it is the first to specifically examine the outcomes of ranibizumab biosimilars for VH secondary to PDR. Until recently, aflibercept has been the most widely used anti-VEGF agent among specialists globally. Given the declining use of ranibizumab, its biosimilars may be perceived as less impactful than aflibercept biosimilars [24]. However, ongoing patent disputes involving aflibercept biosimilars could delay their clinical adoption [25], potentially increasing the relevance and use of ranibizumab biosimilars. In this context, our evaluation of CKD-701 provides meaningful insight into the potential of ranibizumab biosimilars.

However, this study has several limitations. First, its retrospective nature and lack of standardized follow-up or treatment criteria may have introduced bias. Second, the use of uncorrected instead of best-corrected VA may have limited the precision of visual outcomes. In the 22 eyes with available BCVA measurements, a relatively greater degree of visual improvement was observed compared with the uncorrected visual acuity measurements. This may be attributable to the inclusion of cases in which the hemorrhage had sufficiently resolved by the 4-month time point to allow for refraction. Third, the relatively short follow-up period is another major limitation of this study. Previous studies evaluating anti-VEGF therapy for vitreous hemorrhage have generally reported outcomes with follow-up periods of up to approximately 6 months [17, 18]; therefore, our follow-up duration was relatively short. In addition, the limited follow-up restricts the evaluation of long-term outcomes, such as the need for additional injections, delayed vitrectomy, or sustained visual improvement. Fourth, VH severity was evaluated qualitatively rather than quantitatively. Fifth, as the analysis was based solely on CKD-701, the findings may not be applicable to other ranibizumab biosimilars. In addition, VH can sometimes improve spontaneously without active treatment; however, no control group has been established to compare these natural courses. Finally, the study population consisted exclusively of Korean patients, potentially limiting generalizability to other populations.

In summary, in this short-term study, VH secondary to PDR decreased following CKD-701 treatment and was accompanied by visual improvement. Although some patients required vitrectomy, the incidence was comparable with that reported for originator ranibizumab or aflibercept. These findings suggest that CKD-701 can be a treatment option for VH secondary to PDR. Considering the inherent limitations of this study, further prospective studies with strict follow-up and treatment protocols are required to confirm our findings.

Author contributions

Study conception and design (J.H.K.); acquisition of data (S.H.Y., J.C., S.M.P., C.G.K., J.H.K.); analysis and interpretation of data (S.H.Y., J.C., S.M.P., C.G.K., J.H.K.); drafting the article (S.H.Y., J.C., J.H.K.); revising the article critically for important intellectual content (J.H.K.); final approval of the article (S.H.Y., J.C., S.M.P., C.G.K., J.H.K.). S.H.Y. and J.C. equally contributed as co-first authors.

Funding

None.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethical approval and consent to participate

The study was approved by the Institutional Review Board of Kim’s Eye Hospital and was conducted in accordance with the tenets of the Declaration of Helsinki. Due to the retrospective nature of this study, the need for an informed consent was waived off (Kim’s Eye Hospital IRB, Seoul, South Korea).

Consent for publication

Consent for publication was not obtained since no identifying information of the participants was presented in this study.

Competing interests

Jae Hui Kim has received lecture fees from Bayer, Roche, Astellas, Samsung Bioepis, Samil Pharm. Co., Ltd., Chong Kun Dang Pharm. Co., Ltd., and Kukje Pharm. Co., Ltd. The other authors declare no conflicts of interest.